The Department of Veterans Affairs spent more than $150 million dollars on treatment of hypertension in 2000. However, only 50 % of all veterans achieve their blood pressure goals often despite polypharmacy. There is a clear need to develop new treatment strategies for controlling hypertension. The multifunctional calcium/ calmodulin-dependent kinase II (CaMKII) is abundantly expressed in vascular smooth muscle (VSM), however, its role in VSM function has not been intensively investigated. We have developed new, state of the art techniques to study CaMKII function in vascular smooth muscle in vitro and in vitro. Our preliminary data suggest CaMKII as a key regulator in hypertension. Specifically, our preliminary studies show that (1) CaMKII inhibition reduces vascular smooth muscle hypertrophy in vivo and in vitro, and (2) vasoconstrictor response in aorta and resistance blood vessels. (3) Systemic CaMKII blockade reduces Ang-II hypertension. Based on these findings, we hypothesize that (1) CaMKII inhibition in VSM in vivo decreases vascular hypertrophy and vasoconstrictor response in hypertension, (2) CaMKII is required for VSM cell hypertrophy, (2) that CaMKII induces VSM cell hypertrophy by HDAC4 derepression. We will combine a number of complementary, state of the art techniques (molecular biology, protein chemistry, cell signaling and physiology, animal physiology) to dissect the components of CaMKII signaling in VSM and the effect of CaMKII on hypertension and medial hypertrophy in vivo. All of these techniques are at hand in our laboratory or the laboratories of our collaborators. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care Cardiovascular diseases are the most frequent causes of death in the US. Hypertension is an important risk factor for the development of atherosclerosis, stroke and heart failure. Overall, 1.6 million veterans were treated for hypertension in 2002. In 2000, the VA spent an estimated 150 million dollars on antihypertensives alone. Despite these efforts, 50% of all veterans on treatment for hypertension do not reach their blood pressure treatment goals. There is still a pressing need for developing new concepts to treat hypertension. This proposal is aimed at investigating the role of the multifunctional calcium/calmodulin-dependent kinase II (CaMKII) in hypertension, vasomotor response and vascular smooth muscle hypertrophy. Inhibition of CaMKII could represent a novel approach to treating hypertension and preventing vascular remodeling.